Diethylamine was chosen as a representative dialkyl amine for studying the influence of steric hindrance on the course of the reaction Scheme 1 ; Table 4. The desired tertiary N , N -diethylamides were obtained with satisfactory yields even though lower than secondary amides probably due to the steric hindrance of diethylamine Table 4. The results reported in Table 4 also suggested that, when diethyl amine is used as amine component, the reaction is affected by the electronic nature of the substituent on the aromatic ring of the benzoic acid entry r , entry t Table 4 which probably characterize the reactivity of the reaction intermediates.
In fact, the presence of chlorine and nitro group on the aromatic ring of carboxylic acids results in higher yields in amide 18 , 20 , Table 4 than substrates that have no substituents or have electron donor groups on the aromatic ring. This is consistent with the higher reactivity of the involved intermediates in the formation of 18 and In many experiments in which benzoic acid was used, such as in the synthesis of N , N -diethylbenzamide 17 , traces of benzoyl chloride were found in the crude product.
This observation suggested that the acyl chloride could be the reaction intermediate. The amidation reaction could proceed through the formation of an adduct A between the carboxylate ion, generated by the reaction of the carboxylic acid with pyridine, and TiCl 4 Scheme 2 as reported in literature with other metals [ 30 ]. The adduct A is characterized by the presence of a good leaving group that could lead to: a the direct formation of the amide; b the formation of the acyl pyridinium ion B ; c the formation of the acyl chloride C Scheme 2.
B and C could act as additional reaction intermediates for the formation of the amide. In these reactions, steric effects play a key role when both amine and carboxylic acid are sterically hindered. We also explored the stereochemical outcome of the adopted procedure by synthesizing a couple of anilide enantiomers 27 and 28 starting from S N - tert -butoxycarbonylamino propanoic acid N -Boc- l -Alanine and R N - tert -butoxycarbonylamino propanoic acid N -Boc- d -Alanine as acid substrates respectively Scheme 3.
Gratifyingly, we were able to synthesize the two enantiomers with high enantioselectivity. This result demonstrates that this reaction works well also with carboxylic acids bearing acid-labile protecting groups. The comparison of the chromatograms of the single crude enantiomers 27 and 28 Fig. The calculated enantiomeric excess was for both enantiomers satisfactory. A general approach to generate amides has been established using TiCl 4 -induced direct condensation of carboxylic acids with amines.
Our procedure was successfully applied to a broad spectrum of readily available carboxylic acids and amines affording, in short times and after a simple work up, the corresponding amides in high purity and yields. By using N -Boc- l -alanine and its enantiomer N -Boc- d -alanine as chiral carboxylic acids, and aniline as amine component, highly enantiomerically enriched anilides were synthesized, demonstrating that the developed procedure does not generate any significant loss of the optical integrity of the precursors.
The current investigation showed also that this approach works well also with carboxylic acids bearing acid-sensitive groups. All reagents were purchased commercially without further purification. Solvents were purified according to well-known laboratory methods and freshly distilled prior to use. Reaction were carried out in a tightly sealed screw-capped vial. Reactions were magnetically stirred and monitored by thin layer chromatography using Merck-Kieselgel 60 F plates.
Coupling constants J are reported in Hertz Hz Additional file 1. TiCl 4 3 mmol and the amine 1 mmol were added to a solution of carboxylic acid 1 mmol in pyridine 10 mL. Org Biomol Chem — Yu X, Sun D Macrocyclic drugs and synthetic methodologies toward macrocycles. Molecules — J Med Chem — Deming TJ Methodologies for preparation of synthetic block copolypeptides: materials with future promise in drug delivery.
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Chem Commun — Wilson JD, Weingarten H Titanium tetrachloride promoted conversion of carboxylic acids to carboxamides. Can J Chem — Ishihara K, Ohara S, Yamamoto H Direct polycondensation of carboxylic acids and amines catalyzed by 3,4,5-trifluorophenylboronic acid. Macromolecules — Eur J Org Chem — Huang W, Sha WB Direct amide formation from N -arylglycine ethyl esters and carboxylic acids catalysed by phenylboronic acid.
J Chem Res — Werdehausen A, Weiss H Preparation of carboxylic acid amides. Patent Application Pub. Date: Sep. Nordahl A, Carlson R Carboxamides from carboxylic acids by lewis acid catalysis. Acta Chem Scand B — Fetching data from CrossRef. This may take some time to load. Loading related content.
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Try again? In this reaction the carboxylic acid adds to the DCC molecule to form a good leaving group which can then be displaced by an amine during nucleophilic substitution. DCC induced coupling to form an amide linkage is an important reaction in the synthesis of peptides. Complete the reaction map below proposing two different ways to synthesize benzoic acid from benzene.
Steven Farmer Sonoma State University.
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